Clinical studies indicate that a humanized monoclonal antibody against the Epidermal Growth Factor Receptor (EGFR), cetuximab, confers an objective tumor response in a subset of patients with metastatic colorectal cancer. However, most patients do not respond to cetuximab and therefore receive limited or no benefit from this drug. Currently, there is no test that can predict if a cancer will respond to cetuximab. Compelling evidence supports the view that targeting the receptor tyrosine kinases (RTK), particularly those that engage the Phosphoinositide 3-Kinase (PI3K) signaling pathways, is a highly effective strategy for killing for cancers. Accordingly, the therapeutic response to anti-RTK therapy has been shown to be modulated dramatically by the mutational status of key signaling components in the PI3K pathway. The PI3K/Akt signaling pathway drives many epithelial cancers, and its importance in colorectal cancers is underscored by the presence of PIK3CA mutations (the gene encoding for PI3K) in 20-30% of these cancers. PI3K can be activated by multiple different signaling pathways including EGFR, and there is accumulating evidence that EGFR regulates PI3K via distinct mechanisms in cancers sensitive to anti-EGFR therapies. We propose to study the PI3K signaling pathway, biochemically and genetically, in colorectal cancers with the translationa) goal of identifying markers that will predict sensitivity to cetuximab. This will enable the selection of patients that are most likely to benefit from cetuximab. Additionally, these studies may also reveal additional therapeutic targets to enhance cetuximab sensitivity. Our specific aims include: (1) Identify the mechanisms for activating the PI3K/AKT pathway in colorectal cancers;(2) To determine the differences in PI3K regulation between cetuximab sensitive and resistant colorectal cancers in xenograft tumor models;(3) To determine if we can use the information discovered in the first two aims to identify markers that will predict which colorectal cancers will respond to cetuximab. Brief Summary: Cetuximab, a monoclonal antibody against the Epidermal Growth Factor Receptor, is commonly used to treat patients with metastatic colorectal cancer. However, not all patients benefit from this therapy and currently there are no reliable molecular markers to select patients that will benefit. The goal of this project is to find such markers that can be used to select patients most likely to respond to cetuximab.